Global genome nucleotide excision repair (GG-NER) is the major DNA repair system for removing bulky DNA damage induced by environmental carcinogens including solar ultraviolet B (UVB) radiation and air pollutants. Functional GG-NER is essential for maintaining genomic integrity and preventing tumorigenesis in the skin, lung and brain. Promoting GG-NER may have high potential for cancer prevention and therapy. Although the biochemical reactions in damage recognition and repair have been identified, the molecular mechanisms in regulating GG-NER capacity remain largely unknown. Recently, we discovered a novel role for autophagy in promoting GG-NER. As a catabolic process of degrading damaged or unnecessary proteins or organelles, autophagy is a pleiotropic cell survival mechanism with both pro- and anti-tumor effects. The goal of this proposal is to determine the mechanism by which autophagy regulates GG-NER and its impact on UVB-induced skin tumorigenesis and tumor progression. Our recently published work and preliminary data imply that autophagy's enhancement of GG-NER is associated with tumor suppression, and deserves further investigation. Thus we hypothesize that autophagy enhances GG-NER and thus suppresses UVB-induced skin tumorigenesis and tumor progression. To test our hypothesis, we propose the following specific aims. In Aim 1 we will determine the molecular mechanism by which UVB-induced autophagy regulates Twist1. In Aim 2 we will determine the mechanism by which Twist1 suppresses XPC transcription. In Aim 3 we will determine the consequences of autophagy inhibition in UVB-induced skin tumorigenesis and tumor progression in mice. Our team is well positioned to carry out the proposed studies, since we have gained extensive expertise through our recent relevant work and pilot studies, and have created critical reagents and mice for the proposed experiments. Our proposed research may vastly expand our knowledge of GG-NER regulation and tumor suppression by autophagy, and provide new molecular insights for developing potent peptide mimics to promote GG-NER for skin cancer prevention and intervention. Caners arise in the skin more than in any other organ site, most likely due to environmental damage. In addition, our work here in GG-NER and autophagy is not only significant in skin cancer, but is also applicable to other tumor types as well.